U.S. patent number 8,362,029 [Application Number 13/142,784] was granted by the patent office on 2013-01-29 for opioid-containing oral pharmaceutical compositions and methods.
This patent grant is currently assigned to Upsher-Smith Laboratories, Inc.. The grantee listed for this patent is Stephen M. Berge, Kenneth L. Evenstad, James S. Jensen, Victoria Ann O'Neill, Christian F. Wertz. Invention is credited to Stephen M. Berge, Kenneth L. Evenstad, James S. Jensen, Victoria Ann O'Neill, Christian F. Wertz.
United States Patent |
8,362,029 |
Evenstad , et al. |
January 29, 2013 |
Opioid-containing oral pharmaceutical compositions and methods
Abstract
The present invention provides sustained-release oral
pharmaceutical compositions and methods of use. The
sustained-release oral pharmaceutical compositions include an
opioid (including salts thereof) and a salt of a non-steroidal
anti-inflammatory drug (NSAID).
Inventors: |
Evenstad; Kenneth L. (Naples,
FL), Wertz; Christian F. (St. Louis Park, MN), Jensen;
James S. (Edina, MN), O'Neill; Victoria Ann (Wayzata,
MN), Berge; Stephen M. (Shoreview, MN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Evenstad; Kenneth L.
Wertz; Christian F.
Jensen; James S.
O'Neill; Victoria Ann
Berge; Stephen M. |
Naples
St. Louis Park
Edina
Wayzata
Shoreview |
FL
MN
MN
MN
MN |
US
US
US
US
US |
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Assignee: |
Upsher-Smith Laboratories, Inc.
(Maple Grove, MN)
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Family
ID: |
42260778 |
Appl.
No.: |
13/142,784 |
Filed: |
December 31, 2009 |
PCT
Filed: |
December 31, 2009 |
PCT No.: |
PCT/US2009/069902 |
371(c)(1),(2),(4) Date: |
June 29, 2011 |
PCT
Pub. No.: |
WO2010/078486 |
PCT
Pub. Date: |
July 08, 2010 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20110275658 A1 |
Nov 10, 2011 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61141765 |
Dec 31, 2008 |
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Current U.S.
Class: |
514/282; 514/569;
514/289 |
Current CPC
Class: |
A61P
25/04 (20180101); A61K 31/485 (20130101); A61K
31/19 (20130101); A61K 31/135 (20130101); A61K
9/2013 (20130101); A61K 31/439 (20130101); A61K
31/192 (20130101); A61K 31/10 (20130101); A61K
9/2054 (20130101); A61K 31/19 (20130101); A61K
2300/00 (20130101); A61K 31/485 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A01N
43/42 (20060101); A01N 37/10 (20060101); A61K
31/44 (20060101); A61K 31/19 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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37 37 154 |
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Jul 1988 |
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0 009 808 |
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Apr 1980 |
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EP |
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0 546 676 |
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Jun 1993 |
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EP |
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0 649 657 |
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Apr 1995 |
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EP |
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1 384 471 |
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Jan 2004 |
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EP |
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2 074 990 |
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Jul 2009 |
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EP |
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2 085 076 |
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Aug 2009 |
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WO 00/04879 |
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Feb 2000 |
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WO |
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WO/2011/034554 |
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Mar 2011 |
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WO |
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Primary Examiner: Lundgren; Jeffrey S.
Assistant Examiner: Lee; William
Attorney, Agent or Firm: Mueting Raasch & Gebhardt,
P.A.
Parent Case Text
CONTINUING AND RELATED APPLICATION DATA
This application is a U.S. National Stage Application of
International Application No. PCT/US2009/069902, filed on Dec. 31,
2009, published in the English language on Jul. 8, 2010 as
International Publication No. WO 2010/078486 A2, which claims the
benefit of U.S. Provisional Application Ser. No. 61/141,765, filed
Dec. 31, 2008. Attention is also directed to International PCT
Patent Application No. PCT/US2009/069912, filed Dec. 31, 2009,
published in the English language on Mar. 24, 2011 as International
Publication No. WO 2011/034554 A1, which claims the benefit of U.S.
Provisional Application Ser. No. 61/243,391, filed Sep. 17, 2009.
All of the above are incorporated by reference herein.
Claims
What is claimed is:
1. A sustained-release oral pharmaceutical composition comprising
within a single dosage form: a hydrophilic matrix; a
therapeutically effective amount of an opioid; and a salt of a
non-steroidal anti-inflammatory drug (NSAID); wherein the opioid
and the salt of an NSAID are within the hydrophilic matrix; and
wherein the composition exhibits a release profile with respect to
the opioid, wherein the release profile comprises a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions as a result of dissolution of the hydrophilic
matrix.
2. The composition of claim 1 wherein the opioid has analgesic
properties.
3. The composition of claim 1 wherein the opioid comprises a
tertiary amine.
4. The composition of claim 3 wherein the opioid comprises a ring
nitrogen that is a tertiary amine.
5. The composition of claim 1 wherein the opioid is selected from
the group consisting of morphine, codeine, hydromorphone,
hydrocodone, oxycodone, oxymorphone, desomorphine,
diacetylmorphine, buprenorphine, dihydrocodeine, nicomorphine,
benzylmorphine, fentanyl, methadone, tramadol, propoxyphene,
levorphanol, meperidine, and combinations thereof.
6. The composition of claim 1 wherein the opioid is a salt
comprising a hydrochloride, a bitartrate, an acetate, a
naphthylate, a tosylate, a mesylate, a besylate, a succinate, a
palmitate, a stearate, an oleate, a pamoate, a laurate, a valerate,
a hydrobromide, a sulfate, a methane sulfonate, a tartrate, a
citrate, a maleate, or a combination of the foregoing.
7. The composition of claim 1 wherein the NSAID salt is selected
from the group consisting of a salicylate derivative, a 2-aryl
propionic acid derivative, a pyrazolidine derivative, an
N-arylanthranilic acid derivative, an oxicam derivative, an
arylalkanoic acid, an indole derivative, and combinations
thereof.
8. The composition of claim 1 wherein the opioid is present in a
pain-reducing amount.
9. The composition of claim 1 wherein the NSAID salt is present in
an amount effective to provide zero-order release kinetics under in
vitro conditions.
10. The composition of claim 1 wherein the single dosage form is a
tablet form.
11. The composition of claim 1 wherein the hydrophilic matrix
comprises at least one hydrophilic polymeric compound selected from
the group consisting of a gum, a cellulose ether, an acrylic resin,
a polyvinyl pyrrolidone, a protein-derived compound, and
combinations thereof.
12. A sustained-release oral pharmaceutical composition comprising
within a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; and a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, and combinations thereof;
wherein the opioid and the salt of an NSAID are within the
hydrophilic matrix; and wherein the composition exhibits a release
profile with respect to the opioid, wherein the release profile
comprises a substantial portion that is representative of
zero-order release kinetics under in vitro conditions as a result
of dissolution of the hydrophilic matrix.
13. The composition of claim 12 further comprising a
pharmaceutically acceptable anionic surfactant.
14. The composition of claim 13 wherein the pharmaceutically
acceptable anionic surfactant is present in a release-modifying
amount.
15. The composition of claim 13 wherein the pharmaceutically
acceptable anionic surfactant is docusate sodium.
16. The composition of claim 12 wherein the NSAID salt is present
in an amount effective to provide zero-order release kinetics under
in vitro conditions.
17. The composition of claim 12 wherein the single dosage form is a
tablet form.
18. A sustained-release oral pharmaceutical composition comprising
within a single dosage form: a hydrophilic matrix; a
therapeutically effective amount of an opioid; a salt of a
non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid,
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix; and wherein the opioid is released as a result
of dissolution of the hydrophilic matrix.
19. The composition of claim 18 which exhibits a release profile
with respect to the opioid comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions as a result of dissolution of the hydrophilic
matrix.
20. The composition of claim 18 wherein the pharmaceutically
acceptable anionic surfactant is present in a release-modifying
amount.
21. The composition of claim 1 wherein the dosage form comprises:
an uncoated sustained-release core including the hydrophilic
matrix; and an outer coating over the matrix.
22. The composition of claim 21 wherein the outer coating is
substantially uniform.
23. The composition of claim 12 wherein the dosage form comprises:
an uncoated sustained-release core including the hydrophilic
matrix; and an outer coating over the matrix.
24. The composition of claim 23 wherein the outer coating is
substantially uniform.
25. The composition of claim 18 wherein the dosage form comprises:
an uncoated sustained-release core including the hydrophilic
matrix; and an outer coating over the matrix.
26. The composition of claim 25 wherein the outer coating is
substantially uniform.
Description
BACKGROUND
Chronic pain is a major contributor to disability in the
industrialized world and is the cause of an untold amount of
suffering. The successful treatment of severe and chronic pain is a
primary goal of the physician, with opioid analgesics being the
current drugs of choice.
Opioid analgesics (i.e., opioids having analgesic properties) are
drugs that function in a manner similar to that of morphine. These
agents work by binding to opioid receptors, which are found
principally in the central nervous system and the gastrointestinal
tract. Although the term opiate is often used as a synonym for
opioid, it is more frequently used to refer to the natural opium
alkaloids and the semi-synthetics derived from them.
An important goal of analgesic therapy is to achieve continuous
relief of chronic pain. Regular administration of an analgesic is
generally required to ensure that the next dose is given before the
effects of the previous dose have worn off. Compliance with opioids
increases as the required dosing frequency decreases.
Non-compliance results in suboptimal pain control and poor
quality-of-life outcomes. Scheduled rather than "as needed"
administration of opioids is currently recommended in guidelines
for their use in treating chronic non-malignant pain.
Unfortunately, evidence from prior clinical trials and clinical
experience suggests that the short duration of action of
immediate-release opioid formulations would necessitate 4-hourly
administrations in order to maintain optimal levels of analgesia in
patients with chronic pain. Moreover, immediate-release
formulations can exhibit low oral bioavailability. Thus, there is a
need for new opioid-containing oral pharmaceutical compositions
that provide sustained release, and ideally zero-order release
kinetics, and less frequent dosing.
Opioids (particularly those with analgesic activity) are sometimes
the subject of abuse. Typically, a particular dose of an opioid
analgesic is more potent when administered parenterally as compared
to the same dose administered orally. Therefore, one popular mode
of abuse of oral opioid formulations involves the extraction of the
opioid from the dosage form, and the subsequent injection of the
opioid (using any "suitable" vehicle for injection) in order to
achieve a "high." Also, some formulations can be tampered with in
order to provide the opioid contained therein better availability
for illicit use. For example, an opioid-containing tablet can be
crushed in order to render the opioid therein available for
immediate release upon oral, nasal, or intravenous administration.
An opioid formulation can also be abused by administration of more
than the prescribed dose of the drug. Thus, there is a need for new
opioid-containing oral pharmaceutical compositions that provide
abuse deterrence in addition to providing sustained-release,
ideally zero-order release kinetics, and less frequent dosing.
SUMMARY
The present invention provides sustained-release oral
pharmaceutical compositions and methods of use.
In one embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid (including salts thereof); and a salt
of a non-steroidal anti-inflammatory drug (NSAID); wherein the
opioid (including salts thereof) and the salt of an NSAID are
within the hydrophilic matrix; wherein the composition exhibits a
release profile comprising a substantial portion that is
representative of zero-order release kinetics (with respect to the
opioid) under in vitro conditions.
In another embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid (including salts thereof); a salt of
a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid
(including salts thereof), the salt of an NSAID, and the anionic
surfactant are within the hydrophilic matrix. Preferred such
compositions exhibit a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions.
In certain embodiments, the opioid comprises a tertiary amine. In
certain embodiments, the opioid comprises a ring nitrogen that is a
tertiary amine.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; and
a salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; wherein the opioid (including
salts thereof) and the salt of an NSAID are within the hydrophilic
matrix; wherein the composition has a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions.
In another preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; a
salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; and a pharmaceutically
acceptable anionic surfactant selected from the group consisting of
sodium lauryl sulfate, docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferred such compositions have a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In preferred compositions, the opioid is an opioid that has
analgesic activity (i.e., an opioid analgesic). Thus, compositions
of the present invention are preferably used in methods of
preventing, alleviating, or ameliorating the level of pain in a
subject. Alternatively, compositions of the present invention can
be used in suppressing a cough.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; and
a salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; wherein the opioid (including
salts thereof) and the salt of an NSAID are within the hydrophilic
matrix; wherein the composition exhibits a release profile
comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; and a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, and combinations thereof;
wherein the opioid (including salts thereof) and the salt of an
NSAID are within the hydrophilic matrix; wherein the composition
exhibits a release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of tramadol, a salt
thereof, and combinations thereof; and a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; wherein the opioid
(including salts thereof) and the salt of an NSAID are within the
hydrophilic matrix; wherein the composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; a
salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; and a pharmaceutically
acceptable anionic surfactant selected from the group consisting of
sodium lauryl sulfate, docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of tramadol, a salt
thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
In a preferred embodiment, the present invention provides a method
of preventing, alleviating, or ameliorating the level of pain in a
subject, the method administering to a subject a composition
comprising: a hydrophilic matrix; a pain-reducing amount of an
opioid analgesic (including salts thereof); and a salt of a
non-steroidal anti-inflammatory drug (NSAID) present in an amount
effective to provide zero-order release kinetics under in vitro
conditions; wherein the opioid analgesic (including salts thereof)
and salt of an NSAID are within the hydrophilic matrix; wherein the
composition has a release profile comprising a substantial portion
that is representative of zero-order release kinetics under in
vitro conditions.
In a preferred embodiment, the present invention provides a method
of preventing, alleviating, or ameliorating the level of pain in a
subject, the method administering to a subject a composition
comprising: a hydrophilic matrix; a therapeutically effective
amount of an opioid analgesic (including salts thereof); a salt of
a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid
analgesic (including salts thereof), the salt of an NSAID, and the
anionic surfactant are within the hydrophilic matrix. Preferably,
such composition exhibits a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions.
In methods of the present invention, administering a composition of
the present invention comprises administering once or twice per
day, and often once per day.
The terms "comprises" and variations thereof do not have a limiting
meaning where these terms appear in the description and claims.
The words "preferred" and "preferably" refer to embodiments of the
invention that may afford certain benefits, under certain
circumstances. However, other embodiments may also be preferred,
under the same or other circumstances. Furthermore, the recitation
of one or more preferred embodiments does not imply that other
embodiments are not useful, and is not intended to exclude other
embodiments from the scope of the invention.
As used herein, "a," "an," "the," "at least one," and "one or more"
are used interchangeably. Thus, for example, a composition
comprising "a" salt of a non-steroidal anti-inflammatory drug can
be interpreted to mean that the composition includes "one or more"
non-steroidal anti-inflammatory drugs. Similarly, a composition
comprising "a" pharmaceutically acceptable anionic surfactant can
be interpreted to mean that the composition includes "one or more"
pharmaceutically acceptable anionic surfactants.
As used herein, the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates otherwise.
The term "and/or" means one or all of the listed elements or a
combination of any two or more of the listed elements.
Also herein, all numbers are assumed to be modified by the term
"about" and preferably by the term "exactly." Notwithstanding that
the numerical ranges and parameters setting forth the broad scope
of the invention are approximations, the numerical values set forth
in the specific examples are reported as precisely as possible. All
numerical values, however, inherently contain certain errors
necessarily resulting from the standard deviation found in their
respective testing measurements.
Also herein, the recitations of numerical ranges by endpoints
include all numbers subsumed within that range (e.g., 1 to 5
includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Where a range of
values is "up to" a particular value, that value is included within
the range.
The above summary of the present invention is not intended to
describe each disclosed embodiment or every implementation of the
present invention. The description that follows more particularly
exemplifies illustrative embodiments. In several places throughout
the application, guidance is provided through lists of examples,
which examples can be used in various combinations. In each
instance, the recited list serves only as a representative group
and should not be interpreted as an exclusive list.
BRIEF DESCRIPTION OF THE FIGURES
FIGS. 1 and 2 show dissolution profiles in phosphate buffer for
certain tramadol hydrochloride (TMD) formulations in accordance
with embodiments of the present invention.
FIGS. 3 and 4 show dissolution profiles in phosphate buffer for
certain Hydrocodone Bitartrate (HCB) formulations in accordance
with embodiments of the present invention.
FIG. 5 shows dissolution profiles in acidic and hydroalcoholic
media for certain dextromethorphan (DXM) formulations.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present invention provides sustained-release oral
pharmaceutical compositions and methods of use. Preferably, such
compositions are used for pain treatment, cough suppression, or
other indications typically requiring opioid administration. Such
compositions are in a single dosage form and include an opioid
(preferably an opioid analgesic) (including salts thereof), a salt
of a non-steroidal anti-inflammatory drug (NSAID), and a
hydrophilic matrix. Certain embodiments also include a
pharmaceutically acceptable anionic surfactant.
Herein, sustained-release compositions release the opioid over a
period of time greater than 60 minutes. Preferred sustained-release
formulations demonstrate at least 60%, and more preferably at least
80%, release of the opioid over a desired period (e.g., a period of
8 to 12 hours). If desired, however, the formulations of the
present invention could be tailored to release the opioid over any
period from 6 hours to 24 hours or longer.
Particularly preferred sustained-release compositions of the
present invention demonstrate a zero-order release profile with
respect to the opioid under in vitro conditions, such as when
tested in accordance with appropriate United States Pharmacopeia
test methods. Herein, "zero-order" with respect to the opioid
(including salts thereof) means a relatively constant rate of
release (i.e., exhibiting a substantially linear release profile
over a period of time, preferably at least a few hours). Although a
small portion (e.g., the initial 30-60 minutes) of the release
profile may not be zero-order (e.g., as in a formulation containing
an immediate-release coating, or a bilayer or multi-layer
formulation comprising an immediate-release layer), a substantial
portion (e.g., several hours), and preferably a major portion, of
the release profile is representative of zero-order release
kinetics.
Opioids and Salts Thereof
An opioid is a chemical substance that works by binding to opioid
receptors, which are found principally in the central nervous
system and the gastrointestinal tract. The receptors in these two
organ systems mediate both the beneficial effects, and the
undesirable side effects. There are three principal classes of
opioid receptors, .mu., .kappa., .delta. (mu, kappa, and delta),
although up to seventeen have been reported, and include the
.epsilon., , .lamda., and .zeta. (Epsilon, Iota, Lambda and Zeta)
receptors. There are three subtypes of .mu. receptor: .mu..sub.1
and .mu..sub.2, and the newly discovered .mu..sub.3. Another
receptor of clinical importance is the opioid-receptor-like
receptor 1 (ORL1), which is involved in pain responses as well as
having a major role in the development of tolerance to .mu.-opioid
agonists used as analgesics. An opioid can have agonist
characteristics, antagonist characteristics, or both (e.g.,
pentazocine is a synthetic mixed agonist-antagonist opioid
analgesic of the benzomorphan class of opioids used to treat mild
to moderately severe pain). The main use for opioids is for pain
relief, although cough suppression is also a common use. For
example, hydromorphone is used to relieve moderate to severe pain
and severe, painful dry coughing. Hydrocodone is most commonly used
as an intermediate-strength analgesic and strong cough
suppressant.
There are a number of broad classes of opioids: natural opiates,
which are alkaloids contained in the resin of the opium poppy, and
include morphine and codeine; semi-synthetic opiates, created from
the natural opioids, such as hydromorphone (found in Dilaudid),
hydrocodone (found in Vicodin), oxycodone (found in Oxycontin and
Percocet), oxymorphone, desomorphine, diacetylmorphine (Heroin),
nicomorphine, buprenorphine, dihydrocodeine, and benzylmorphine;
and fully synthetic opioids, such as fentanyl, methadone, tramadol,
and propoxyphene (found in Darvon and Darvocet N). Other examples
of opioids include levorphanol, meperidine (found in Demerol),
pentazocine, tilidine, and others disclosed, for example, at
www.opioids.com.
Certain opioids have antagonist action. For example, naloxone is a
.mu.-opioid receptor competitive antagonist. Naloxone is a drug
used to counter the effects of opioid overdose, for example heroin
or morphine overdose. Naltrexone is an opioid receptor antagonist
used primarily in the management of alcohol dependence and opioid
dependence. N-methyl naltrexone is also an opioid receptor
antagonist.
Various combinations of such compounds can be used if desired. Each
of these compounds includes a tertiary amine as shown, wherein the
amine nitrogen may or may not be within a ring:
##STR00001## ##STR00002## ##STR00003##
Preferred opioids are opioid analgesics, which have morphine-like
activity and produce bodily effects including pain relief and
sedation. For certain embodiments, the opioid, particularly opioid
analgesic, selected for use in compositions of the present
invention is one having a tertiary amine nitrogen. For certain
embodiments, the opioid, particularly opioid analgesic, selected
includes a ring nitrogen that is a tertiary amine.
The opioids can be used in a variety of salt forms including
"pharmaceutically acceptable salts." Preparation of such salts is
well-known to those skilled in pharmaceuticals. Examples of
suitable pharmaceutically acceptable salts include, but are not
limited to, hydrochlorides, bitartrates, acetates, naphthylates,
tosylates, mesylates, besylates, succinates, palmitates, stearates,
oleates, pamoates, laurates, valerates, hydrobromides, sulfates,
methane sulfonates, tartrates, citrates, maleates, and the like, or
combinations of any of the foregoing. Preferably, the opioid is
selected from the group consisting of hydrocodone (e.g.,
hydrocodone bitartrate), tramadol (e.g., tramadol hydrochloride),
and combinations thereof. For certain embodiments, the opioid is
hydrocodone (particularly hydrocodone bitartrate). For certain
embodiments, the opioid is tramadol (particularly tramadol
hydrochloride).
An opioid, particularly an opioid analgesic, is used herein in a
therapeutically effective amount. Determination of a
therapeutically effective amount will be determined by the
condition being treated (e.g., pain or cough) and on the target
dosing regimen (e.g., once per day, twice per day). Determination
of such an amount is well within the capability of those skilled in
the art, especially in light of the detailed disclosure provided
herein. For example, if the composition is used as a cough
suppressant, the amount of the opioid would be that which is
effective for suppressing a cough. If the composition is used to
treat pain, a therapeutically effective amount or an opioid is
referred to herein as a "pain-reducing amount." Herein, this means
an amount of compound effective to reduce or treat (i.e., prevent,
alleviate, or ameliorate) pain symptoms over the desired time
period. This amount can vary with each specific opioid depending on
the potency of each. For example, for hydrocodone, the amount per
single dosage form of the present invention may be 5 mg to 50
mg.
Salts of Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
Compositions of the present invention include one or more
non-steroidal anti-inflammatory drugs, usually abbreviated to
NSAIDs or NAIDs. These are drugs with analgesic, antipyretic and,
in higher doses, anti-inflammatory effects.
NSAIDs are sometimes also referred to as non-steroidal
anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal
anti-inflammatory medicines (NSAIMs). All NSAIDs as used herein are
nonspecific COX inhibitors.
Surprisingly, in the practice of the present invention, salts of
NSAIDs (but not the free bases) provide compositions with
zero-order release kinetics with respect to the opioids (including
salts thereof).
There are roughly seven major classes of NSAIDs, including:
(1) salicylate derivatives, such as acetylsalicylic acid (aspirin),
amoxiprin, benorylate/benorilate, choline magnesium salicylate,
diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium
salicylate, salicyl salicylate, and salicylamide; a few structures
of such compounds are as follows:
##STR00004##
(2) 2-aryl propionic acid derivatives, such as ibuprofen,
ketoprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen,
fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam,
ondoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen,
suprofen, and tiaprofenic acid; a few structures of such compounds
are as follows:
##STR00005##
(3) pyrazolidine derivatives, such as phenylbutazone, ampyrone,
azapropazone, clofezone, kebuzone, metamizole, mofebutazone,
oxyphenbutazone, phenazone, and sulfinpyrazone; a few structures of
such compounds are as follows:
##STR00006##
(4) N-arylanthranilic acid (or fenamate) derivatives, such as
mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic
acid, and esters thereof; a few structures of such compounds are as
follows:
##STR00007##
(5) oxicam derivatives, such as piroxicam, droxicam, lornoxicam,
meloxicam, and tenoxicam; a few structures of such compounds are as
follows:
##STR00008##
(6) arylalkanoic acids, such as diclofenac, aceclofenac,
acemethacin, alclofenac, bromfenac, etodolac, indomethacin,
nabumetone, oxametacin, proglumetacin, sulindac (prodrug), and
tolmetin; a few structures of such compounds are as follows:
##STR00009##
(7) indole derivatives, such as indomethacin, the structure of
which is as follows:
##STR00010##
Although acetaminophen (paracetamol) is an analgesic and it is
sometimes grouped with NSAIDs, it is not an NSAID (particularly for
the purposes of the present invention) because it does not have any
significant anti-inflammatory activity.
NSAIDs used in compositions of the present invention are
pharmaceutically acceptable salts thereof. Typically, such salts
include metal salts, such as sodium, calcium, or potassium salts.
Salts such as bismuth salts, magnesium salts, or zinc salts may
also be suitable. Various combinations of counterions and/or NSAID
salts can be used if desired.
Preferred NSAID salts include a terminal carboxylic acid or
terminal carboxylate group on the active moiety. In certain
embodiments, the NSAID salts include a terminal carboxylic acid
group on the active moiety. In certain embodiments, the NSAID salts
include a terminal carboxylate group on the active moiety.
Exemplary such NSAID salts are selected from the group consisting
of a salicylate derivative, a 2-aryl propionic acid derivative, an
N-arylanthranilic acid derivative, an aryl alkanoic acid, an indole
derivative, and combinations thereof. Preferred NSAID salts include
salts of 2-aryl propionic acid derivative (e.g., naproxen and
ibuprofen), aryl alkanoic acids, or combinations thereof.
Particularly preferred NSAID salts include naproxen sodium,
ibuprofen sodium, diclofenac sodium, and combinations thereof.
Structures of naproxen, diclofenac, and ibuprofen are as
follows:
##STR00011##
In preferred compositions, an NSAID salt is present in compositions
of the present invention in an amount to provide zero-order release
kinetics under in vitro conditions. Such amount can be a
sub-therapeutic amount or it can be a conventional therapeutic
amount. Determination of such an amount is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein. For example, naproxen sodium
could be included in a single dosage form of the current invention
at an amount of 220 mg to 750 mg (for a twice per day dosage
form).
Pharmaceutically Acceptable Anionic Surfactants
Suitable pharmaceutically acceptable anionic surfactants include,
for example, monovalent alkyl carboxylates, acyl lactylates, alkyl
ether carboxylates, N-acyl sarcosinates, polyvalent alkyl
carbonates, N-acyl glutamates, fatty acid-polypeptide condensates,
sulfur-containing surfactants (e.g., sulfuric acid esters, alkyl
sulfates such as sodium lauryl sulfate (SLS), ethoxylated alkyl
sulfates, ester linked sulfonates such as docusate sodium or
dioctyl sodium succinate (DSS), and alpha olefin sulfonates), and
phosphated ethoxylated alcohols. Preferred surfactants are on the
GRAS ("Generally Recognized as Safe") list. Various combinations of
pharmaceutically acceptable anionic surfactants can be used if
desired.
In certain embodiments, the pharmaceutically acceptable anionic
surfactant is a sulfur-containing surfactant, and particularly an
alkyl sulfate, an ester-linked sulfonate, and combinations thereof.
Preferred pharmaceutically acceptable anionic surfactants include
sodium lauryl sulfate, docusate (i.e., dioctyl sulfosuccinate)
sodium, docusate calcium, and combinations thereof. A particularly
preferred anionic surfactant is docusate sodium. The structures of
docusate sodium and sodium lauryl sulfate are as follows:
##STR00012##
In preferred embodiments, a pharmaceutically acceptable anionic
surfactant is present in compositions of the present invention in a
release-modifying amount. A wide range of amounts can be used to
tailor the rate and extent of release. Determination of such an
amount is well within the capability of those skilled in the art,
especially in light of the detailed disclosure provided herein.
In some embodiments, certain surfactants such as docusate can
function as a stool softener when used at a therapeutic level;
however, sub-therapeutic amounts can be used for release
modification.
Such surfactants can be used for their abuse deterrence effects.
For example, a surfactant could function as a nasal irritant, which
would make crushing and inhaling the compositions undesirable.
Also, a mixture of an opioid and a surfactant (e.g., docusate) in a
hydrophilic matrix is difficult to extract and separate into the
individual components, and injection of the mixture is undesirable
and/or unsafe.
Hydrophilic Matrix and Other Excipients
Compositions of the present invention include a hydrophilic matrix,
wherein the opioid (including salts thereof), the salt of an NSAID,
and the optional anionic surfactant are within (e.g., mixed within)
the hydrophilic matrix. Such matrix preferably includes at least
one hydrophilic polymeric compound. The hydrophilic polymeric
compound preferably forms a matrix that releases the opioid,
preferably opioid analgesic, or the pharmaceutically acceptable
salt thereof at a sustained rate upon exposure to liquids. The rate
of release of the opioid or the pharmaceutically acceptable salt
thereof from the hydrophilic matrix typically depends, at least in
part, on the opioid's partition coefficient between the components
of the hydrophilic matrix and the aqueous phase within the
gastrointestinal tract.
The sustained-release composition generally includes at least one
hydrophilic polymeric compound in an amount of 10% to 90% by
weight, preferably in an amount of 20% to 80% by weight, based on
the total weight of the composition.
The hydrophilic polymeric compound may be any known in the art.
Exemplary hydrophilic polymeric compounds include gums, cellulose
ethers, acrylic resins, polyvinyl pyrrolidone, protein-derived
compounds, and combinations thereof. Exemplary gums include
heteropolysaccharide gums and homopolysaccharide gums, such as
xanthan, tragacanth, pectins, acacia, karaya, alginates, agar,
guar, hydroxypropyl guar, carrageenan, locust bean gums, and gellan
gums. Exemplary cellulose ethers include hydroxyalkyl celluloses
and carboxyalkyl celluloses. Preferred cellulose ethers include
hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl
methylcelluloses, carboxy methylcelluloses, and mixtures thereof.
Exemplary acrylic resins include polymers and copolymers of acrylic
acid, methacrylic acid, methyl acrylate, and methyl methacrylate.
Various combinations of hydrophilic compounds can be used for
various effects.
In some embodiments, the hydrophilic compound is preferably a
cellulose ether. Exemplary cellulose ethers include those
commercially available under the trade designation METHOCEL Premium
from Dow Chemical Co. Such methylcellulose and hypromellose (i.e.,
hydroxypropyl methylcellulose) products are a broad range of
water-soluble cellulose ethers that enable pharmaceutical
developers to create formulas for tablet coatings, granulation,
sustained release, extrusion, and molding. For certain embodiments,
the cellulose ether comprises a hydroxypropyl methylcellulose.
Varying the types of cellulose ethers can impact the release rate.
For example, varying the types of METHOCEL cellulose ethers, which
have different viscosities of 2% solutions in water (METHOCEL K4M
Premium hypromellose 2208 (19-24% methoxy content; 7-12%
hydroxypropyl content; 3,000-5,600 cps of a 2% solution in water);
METHOCEL K15M Premium hypromellose 2208 (19-24% methoxy content;
7-12% hydroxypropyl content; 11,250-21,000 cps of a 2% solution in
water); and METHOCEL K100M Premium hypromellose 2208 (19-24%
methoxy content; 7-12% hydroxypropyl content; 80,000-120,000 cps of
a 2% solution in water)) can help tailor release rates.
Compositions of the present invention can also include one or more
excipients such as lubricants, glidants, flavorants, coloring
agents, stabilizers, binders, fillers, disintegrants, diluents,
suspending agents, viscosity enhancers, wetting agents, buffering
agents, control release agents, crosslinking agents, preservatives,
and the like. Such compounds are well known in the art of drug
release and can be used in various combinations.
One particularly useful excipient that can form at least a portion
of a composition of the present invention is a binder that
includes, for example, a cellulose such as microcrystalline
cellulose. An exemplary microcrystalline cellulose is that
available under the trade designation AVICEL PH (e.g., AVICEL
PH-101, AVICEL PH-102, AVICEL PH-301, AVICEL PH-302, and AVICEL
RC-591) from FMC BioPolymers. The sustained-release composition
generally includes at least one microcrystalline cellulose in an
amount of 3 wt-% to 50 wt-%, based on the total weight of the
composition.
Other additives can be incorporated into compositions of the
present invention to further modify the rate and extent of release.
For example, a non-pharmacologically active amine, such as
tromethamine, triethanolamine, betaine, benzathine, or erbumine
could be included in the compositions of the present invention to
further modify the release rate.
Compositions of the present invention can optionally include
compounds that function as abuse deterrents. For example, opioid
antagonists (e.g., naltrexone, N-methylnaltrexone, naloxone) can be
combined with opioid agonists to deter parenteral abuse of opioid
agonists. Such opioid agonist/antagonist combinations can be chosen
such that the opioid agonist and opioid antagonist are only
extractable from the dosage form together, and at least a two-step
extraction process is required to separate the opioid antagonist
from the opioid agonist. The amount of opioid antagonist is
sufficient to counteract opioid effects if extracted together and
administered parenterally and/or the amount of antagonist is
sufficient to cause the opioid agonist/antagonist combination to
provide an aversive effect in a physically dependent human subject
when the dosage form is orally administered. Typically, such
compositions are formulated in such a way that if the dosage form
is not tampered with, the antagonist passes through the GI tract
intact; however, upon crushing, chewing, dissolving, etc., the
euphoria-curbing antagonist is released.
In a similar fashion, compounds that cause nausea could be added to
the formulation to prevent abusers from taking more than the
intended dose. These components are added to the formulation at
sub-therapeutic levels, such that no adverse effects are realized
when the correct dose is taken.
Also, compositions of the present invention can include an aversive
agent such as a dye (e.g., one that stains the mucous membrane of
the nose and/or mouth) that is released when the dosage form is
tampered with and provides a noticeable color or dye which makes
the act of abuse visible to the abuser and to others such that the
abuser is less likely to inhale, inject, and/or swallow the
tampered dosage form. Examples of various dyes that can be employed
as the aversive agent, including for example, and without
limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C
Yellow No. 6, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Green No. 1, FD&C Green No. 3, FD&C Green No. 5, FD&C
Red No. 30, D&C Orange No. 5, D&C Red No. 8, D&C Red
No. 33, caramel, and ferric oxide, red, other FD&C dyes and
lakes, and natural coloring agents such as grape skin extract, beet
red powder, beta-carotene, annato, carmine, turmeric, paprika, and
combinations thereof.
The sustained-release compositions of the present invention may
also include one or more hydrophobic polymers. The hydrophobic
polymers may be used in an amount sufficient to slow the hydration
of the hydrophilic compound without disrupting it. For example, the
hydrophobic polymer may be present in an amount of 0.5% to 20% by
weight, based on the total weight of the composition.
Exemplary hydrophobic polymers include alkyl celluloses (e.g.,
C.sub.1-6 alkyl celluloses, carboxymethylcellulose,
ethylcellulose), other hydrophobic cellulosic materials or
compounds (e.g., cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers
(e.g., polyvinyl acetate phthalate), polymers or copolymers derived
from acrylic and/or methacrylic acid esters, zein, waxes (e.g.,
carnauba wax), shellac, hydrogenated vegetable oils, and
combinations thereof.
Pharmaceutical Compositions
Pharmaceutical compositions of the present invention are single
dosage forms that can be in a form capable of providing sustained
release of the opioid. Herein, a "single dosage form" refers to the
components of the composition be included within one physical unit
(e.g., one tablet), whether it be in a uniform matrix, a
multilayered construction, or some other configuration. Most
commonly, this includes a tablet, which can include molded tablets,
compressed tablets, or freeze-dried tablets. Other possible solid
forms include pills, pellets, particulate forms (e.g., beads,
powders, granules), and capsules (e.g., with particulate
therein).
A single dosage form can be a coated dosage form with, for example,
an outer layer of an immediate-release (IR) material (e.g., an
opioid, an NSAID, or both, a release-modifying agent, a film
coating for taste masking or for ease of swallowing, or the like),
with a sustained-release (SR) core. Typically, such coated
formulations do not demonstrate zero-order release kinetics during
the initial immediate-release phase, but preferably demonstrate
zero-order release kinetics during the dissolution of the
sustained-release core.
A single dosage form can be incorporated into a multi-layered
dosage form (e.g., tablet). For example, a bilayer tablet could be
formulated to include a layer of a conventional immediate-release
matrix and a layer of a sustained-release composition of the
present invention. Optionally, a multi-layered dosage form could be
coated.
Pharmaceutical compositions for use in accordance with the present
invention may be formulated in a conventional manner to incorporate
one or more physiologically acceptable carriers comprising
excipients and auxiliaries. Compositions of the invention may be
formulated as tablets, pills, capsules, and the like, for oral
ingestion by a patient to be treated.
Pharmaceutical compositions of the present invention may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, granulating, encapsulating, entrapping, or
tabletting processes.
Pharmaceutical compositions suitable for use in the present
invention include compositions where the ingredients are contained
in an amount effective to achieve its intended purpose. The exact
formulation, route of administration, and dosage for the
pharmaceutical compositions of the present invention can be chosen
by the individual physician in view of the patient's condition.
(See, e.g., Fingl et al. in "The Pharmacological Basis of
Therapeutics", Ch. 1, p. 1 (1975)). The exact dosage will be
determined on a drug-by-drug basis, in most cases. Dosage amount
and interval may be adjusted individually to provide plasma levels
of the active ingredients/moieties that are sufficient to maintain
the modulating effects, or minimal effective concentration (MEC).
The MEC will vary for each compound but can be estimated from in
vitro data. Dosages necessary to achieve the MEC will depend on
individual characteristics and route of administration. However,
HPLC assays or bioassays can be used to determine plasma
concentrations. The amount of composition administered will, of
course, be dependent on the subject being treated, on the subject's
weight, the severity of the pain, the manner of administration, and
the judgment of the prescribing physician.
The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert.
It will be understood by those of skill in the art that numerous
and various modifications can be made without departing from the
spirit of the present invention. Therefore, it should be clearly
understood that the forms of the present invention are illustrative
only and are not intended to limit the scope of the present
invention.
Exemplary Embodiments of the Invention
1. A sustained-release oral pharmaceutical composition comprising
within a single dosage form: a hydrophilic matrix; a
therapeutically effective amount of an opioid (including salts
thereof); and a salt of a non-steroidal anti-inflammatory drug
(NSAID); wherein the opioid and the salt of an NSAID are within the
hydrophilic matrix; and wherein the composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions. 2. A
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid (including salts thereof); a salt of
a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid,
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. 3. The composition of embodiment 2 which
exhibits a release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. 4. The composition of any one of embodiments 1 through
3 wherein the opioid has analgesic properties. 5. The composition
of any one of embodiments 1 through 4 wherein the opioid comprises
a tertiary amine. 6. The composition of embodiment 5 wherein the
opioid comprises a ring nitrogen that is a tertiary amine. 7. The
composition of any one of embodiments 1 through 6 wherein the
opioid is selected from the group consisting of morphine, codeine,
hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine,
diacetylmorphine, buprenorphine, dihydrocodeine, nicomorphine,
benzylmorphine, fentanyl, methadone, tramadol, propoxyphene,
levorphanol, meperidine, and combinations thereof. 8. The
composition of any one of embodiments 1 through 7 wherein the
opioid is a salt comprising a hydrochloride, a bitartrate, an
acetate, a naphthylate, a tosylate, a mesylate, a besylate, a
succinate, a palmitate, a stearate, an oleate, a pamoate, a
laurate, a valerate, a hydrobromide, a sulfate, a methane
sulfonate, a tartrate, a citrate, a maleate, or a combination of
the foregoing. 9. The composition of embodiment 7 or embodiment 8
wherein the opioid is selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof. 10.
The composition of embodiment 9 wherein the opioid is selected from
the group consisting of hydrocodone bitartrate, tramadol
hydrochloride, and combinations thereof. 11. The composition of any
one of embodiments 7 through 9 wherein the opioid is selected from
the group consisting of hydrocodone, a salt thereof, and
combinations thereof. 12. The composition of embodiment 11 wherein
the opioid comprises hydrocodone bitartrate. 13. The composition of
any one of embodiments 7 through 9 wherein the opioid is selected
from the group consisting of tramadol, a salt thereof, and
combinations thereof. 14. The composition of embodiment 13 wherein
the opioid comprises tramadol hydrochloride. 15. The composition of
any one of the preceding embodiments wherein the NSAID salt is
selected from the group consisting of a salicylate derivative, a
2-aryl propionic acid derivative, a pyrazolidine derivative, an
N-arylanthranilic acid derivative, an oxicam derivative, an
arylalkanoic acid, an indole derivative, and combinations thereof.
16. The composition of embodiment 15 wherein the NSAID salt
comprises a terminal carboxylic acid group or terminal carboxylate
group. 17. The composition of embodiment 16 wherein the NSAID salt
is selected from the group consisting of a salicylate derivative, a
2-aryl propionic acid derivative, an N-arylanthranilic acid
derivative, an aryl alkanoic acid, an indole derivative, and
combinations thereof. 18. The composition of embodiment 17 wherein
the NSAID salt is a 2-aryl propionic acid derivative, an aryl
alkanoic acid, or combinations thereof. 19. The composition of
embodiment 18 wherein the NSAID salt is selected from the group
consisting of a salt of naproxen, diclofenac, ibuprofen, and
combinations thereof. 20. The composition of embodiment 19 wherein
the NSAID salt is selected from the group consisting of naproxen
sodium, diclofenac sodium, ibuprofen sodium, and combinations
thereof. 21. The composition of any one of embodiments 2 through
20, as they depend on embodiment 2, wherein the pharmaceutically
acceptable anionic surfactant is selected from the group consisting
of monovalent alkyl carboxylates, acyl lactylates, alkyl ether
carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates,
N-acyl glutamates, fatty acid-polypeptide condensates,
sulfur-containing surfactants, phosphated ethoxylated alcohols, and
combinations thereof. 22. The composition of embodiment 21 wherein
the pharmaceutically acceptable anionic surfactant is a
sulfur-containing surfactant. 23. The composition of embodiment 22
wherein the sulfur-containing surfactant is selected from the group
consisting of an alkyl sulfate, an ester-linked sulfonate, and
combinations thereof. 24. The composition of embodiment 23 wherein
the pharmaceutically acceptable anionic surfactant is selected from
the group consisting of sodium lauryl sulfate, docusate sodium,
docusate calcium, and combinations thereof 25. The composition of
embodiment 24 wherein the pharmaceutically acceptable anionic
surfactant is docusate sodium. 26. The composition of any one of
the preceding embodiments wherein the opioid is present in a
pain-reducing amount. 27. The composition of any one of the
preceding embodiments wherein the NSAID salt is present in an
amount effective to provide zero-order release kinetics under in
vitro conditions. 28. The composition of any one of the preceding
embodiments wherein the pharmaceutically acceptable anionic
surfactant is present in a release-modifying amount. 29. The
composition of any one of the preceding embodiments wherein the
single dosage form is a tablet form. 30. The composition of
embodiment 29 wherein the single dosage form tablet comprises a
unitary matrix. 31. The composition of embodiment 29 wherein the
single dosage form tablet comprises a multilayer tablet. 32. The
composition of embodiment 31 wherein the single dosage form
comprises an outer layer of an immediate-release (IR) material and
a sustained-release (SR) core. 33. The composition of embodiment 32
wherein the IR material comprises an opioid, an NSAID, or both. 34.
The composition of any one of the previous embodiments wherein the
hydrophilic matrix comprises at least one hydrophilic polymeric
compound selected from the group consisting of a gum, a cellulose
ether, an acrylic resin, a polyvinyl pyrrolidone, a protein-derived
compound, and combinations thereof. 35. The composition of
embodiment 34 wherein the hydrophilic polymeric compound comprises
a cellulose ether. 36. The composition of embodiment 35 wherein the
cellulose ether comprises a hydroxyalkyl cellulose, a carboxyalkyl
cellulose, and combinations thereof. 37. The composition of
embodiment 35 wherein the cellulose ether comprises a
methylcellulose, a hydroxypropyl methylcellulose, and combinations
thereof. 38. The composition of embodiment 37 wherein the cellulose
ether comprises a hydroxypropyl methylcellulose. 39. The
composition of any one of the previous embodiments further
including one or more excipients. 40. The composition of embodiment
39 wherein the excipients comprise lubricants, glidants,
flavorants, coloring agents, stabilizers, binders, fillers,
disintegrants, diluents, suspending agents, viscosity enhancers,
wetting agents, buffering agents, control release agents,
crosslinking agents, preservatives, and combinations thereof. 41.
The composition of embodiment 40 comprising a binder. 42. The
composition of embodiment 41 wherein the binder comprises a
microcrystalline cellulose. 43. A sustained-release oral
pharmaceutical composition comprising within a single dosage form:
a hydrophilic matrix; a therapeutically effective amount of an
opioid selected from the group consisting of hydrocodone, tramadol,
salts thereof, and combinations thereof; and a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, diclofenac, ibuprofen, and
combinations thereof; wherein the opioid and the salt of an NSAID
are within the hydrophilic matrix; and wherein the composition
exhibits a release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. 44. The composition of embodiment 43 wherein the opioid
is selected from the group consisting of hydrocodone, a salt
thereof, and combinations thereof. 45. The composition of
embodiment 44 wherein the opioid comprises hydrocodone bitartrate.
46. The composition of embodiment 43 wherein the opioid is selected
from the group consisting of tramadol, a salt thereof, and
combinations thereof. 47. The composition of embodiment 46 wherein
the opioid comprises tramadol hydrochloride. 48. The composition of
any one of embodiments 43 through 47 wherein the NSAID salt is
selected from the group consisting of naproxen sodium, diclofenac
sodium, ibuprofen sodium, and combinations thereof. 49. The
composition of any one of embodiments 43 through 48 wherein the
hydrophilic polymeric compound comprises a cellulose ether. 50. The
composition of embodiment 49 wherein the cellulose ether comprises
a hydroxyalkyl cellulose, a carboxyalkyl cellulose, and
combinations thereof. 51. The composition of embodiment 50 wherein
the cellulose ether comprises a methylcellulose, a hydroxypropyl
methylcellulose, and combinations thereof. 52. The composition of
embodiment 51 wherein the cellulose ether comprises a hydroxypropyl
methylcellulose. 53. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: a hydrophilic
matrix comprising a hydroxypropyl methylcellulose; a
therapeutically effective amount of an opioid selected from the
group consisting of hydrocodone, a salt thereof, and combinations
thereof; and a salt of a non-steroidal anti-inflammatory drug
(NSAID) selected from the group consisting of a salt of naproxen,
and combinations thereof; wherein the opioid and the salt of an
NSAID are within the hydrophilic matrix; and wherein the
composition exhibits a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions. 54. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: a hydrophilic
matrix comprising a hydroxypropyl methylcellulose; a
therapeutically effective amount of an opioid selected from the
group consisting of tramadol, a salt thereof, and combinations
thereof; and a salt of a non-steroidal anti-inflammatory drug
(NSAID) selected from the group consisting of a salt of naproxen,
and combinations thereof; wherein the opioid and the salt of an
NSAID are within the hydrophilic matrix; and wherein the
composition exhibits a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions. 55. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: a hydrophilic
matrix; a therapeutically effective amount of an opioid selected
from the group consisting of hydrocodone, tramadol, salts thereof,
and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, diclofenac, ibuprofen, and combinations
thereof; and a pharmaceutically acceptable anionic surfactant
selected from the group consisting of sodium lauryl sulfate,
docusate sodium, docusate calcium, and combinations thereof;
wherein the opioid, the salt of an NSAID, and the anionic
surfactant are within the hydrophilic matrix. 56. The composition
of embodiment 55 which exhibits a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions. 57. The composition of
embodiment 55 or embodiment 56 wherein the opioid is selected from
the group consisting of hydrocodone, a salt thereof, and
combinations thereof. 58. The composition of embodiment 57 wherein
the opioid comprises hydrocodone bitartrate. 59. The composition of
embodiment 55 or embodiment 56 wherein the opioid is selected from
the group consisting of tramadol, a salt thereof, and combinations
thereof. 60. The composition of embodiment 59 wherein the opioid
comprises tramadol hydrochloride. 61. The composition of any one of
embodiments 55 through 60 wherein the pharmaceutically acceptable
anionic surfactant is docusate sodium. 62. The composition of any
one of embodiments 55 through 61 wherein the hydrophilic polymeric
compound comprises a cellulose ether. 63. The composition of
embodiment 62 wherein the cellulose ether comprises a hydroxyalkyl
cellulose, a carboxyalkyl cellulose, and combinations thereof. 64.
The composition of embodiment 63 wherein the cellulose ether
comprises a methylcellulose, a hydroxypropyl methylcellulose, and
combinations thereof. 65. The composition of embodiment 64 wherein
the cellulose ether comprises a hydroxypropyl methylcellulose. 66.
A sustained-release oral pharmaceutical composition comprising
within a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid, the salt of an NSAID, and
the anionic surfactant are within the hydrophilic matrix. 67. A
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of tramadol, a salt
thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid, the salt of an NSAID, and
the anionic surfactant are within the hydrophilic matrix. 68. The
composition of embodiment 66 or embodiment 67 which exhibits a
release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. 69. A method of preventing, alleviating, or
ameliorating the level of pain in a subject, the method comprising
administering to a subject a composition of any one of embodiments
1 through 68. 70. A method of suppressing cough in a subject, the
method comprising administering to a subject a composition of any
one of embodiments 1 through 68. 71. A method of preventing,
alleviating, or ameliorating the level of pain in a subject, the
method administering to a subject a composition comprising: a
hydrophilic matrix; a pain-reducing amount of an opioid analgesic
(including salts thereof); and a salt of a non-steroidal
anti-inflammatory drug (NSAID) present in an amount effective to
provide zero-order release kinetics under in vitro conditions;
wherein the opioid analgesic and the salt of an NSAID are within
the hydrophilic matrix; and wherein the composition has a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions. 72. A method
of preventing, alleviating, or ameliorating the level of pain in a
subject, the method administering to a subject a composition
comprising: a hydrophilic matrix; a therapeutically effective
amount of an opioid analgesic (including salts thereof); a salt of
a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid
analgesic, the salt of an NSAID, and the anionic surfactant are
within the hydrophilic matrix. 73. The method of embodiment 72
which has a release profile comprising a substantial portion that
is representative of zero-order release kinetics under in vitro
conditions. 74. The method of any one of embodiments 69 through 73
wherein administering the composition comprises administering once
or twice per day. 75. The method of embodiment 74 wherein
administering the composition comprises administering once per
day.
EXAMPLES
Objects and advantages of this invention are further illustrated by
the following examples, but the particular materials and amounts
thereof recited in these examples, as well as other conditions and
details, should not be construed to unduly limit this
invention.
Example 1
Preparation of Sustained-Release Hydrophilic Matrix Tablets
Containing Tramadol Hydrochloride (TMD), Naproxen Sodium (NAP), and
Docusate Sodium (DSS) at Benchtop Scale
Each hydrophilic matrix tablet lot was produced by thy-blending the
active substance(s) and excipients together followed by direct
compression. The TMD and NAP (when present) were added together
with all excipients in an HDPE bag. Blending was accomplished by
manually mixing the contents of the bag for five minutes. Aliquots
of the blend were massed out using an analytical balance and were
compressed using a Manesty DC16 press. Each tablet aliquot was
added to the die manually and compressed at a speed of 5 rpm. Lots
without NAP were compressed using 0.3125-inch round, concave Natoli
tooling (HOB No. 91300), while lots containing NAP were compressed
using 0.3750-inch round, concave Natoli tooling (HOB No. 91380).
The compression force was varied until a tablet breaking force of
14-16 kPa was consistently achieved.
TABLE-US-00001 TABLE 1 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Tramadol Methocel Naproxen
Granular Total Hydrochloride K4M Avicel PH- Sodium Docusate Tablet
(Spectrum Chemical (Dow 302 (FMC (Albemarle Sodium (Cytec Mass Lot
No. Manufacturing Corp. Chemical) Biopolymer) Corp.) Industries,
Inc.) (mg) Prototype 1 15.0 120.0 45.0 180.0 Prototype 2 15.0 120.0
45.0 17.6 197.6 Prototype 3 15.0 120.0 45.0 117.7 297.7 Prototype 4
15.0 120.0 45.0 220.0 400.0 Prototype 5 15.0 120.0 45.0 220.0 8.8
408.8 Prototype 6 15.0 120.0 45.0 220.0 17.6 417.6 Prototype 7 15.0
120.0 45.0 220.0 29.4 429.4 Prototype 8 15.0 120.0 45.0 220.0 117.7
517.7
USP Apparatus 2 was used for the dissolution testing of the
prototype tablets produced. The dissolution samples were assayed
for TMD using HPLC with UV detection at 280 nm. The system
parameters for both the chromatographic and dissolution analysis
are shown below. System: Hewlett Packard 1100 Series HPLC System
Column: Phenomenex Jupiter C18, 250.times.4.6 mm ID, 5.mu., 300
.ANG. Part No.: 00G-4053-EO Detector: UV detector, 280 nm Mobile
Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA Mobile Phase B:
Pure methanol Method Type: Gradient Flow Rate: 1.5 mL/min Injection
Volume: 30 .mu.l Run Time: 8.00 minutes (8.01-10.00 minutes is
reequilibration) Peakwidth: >0.1 min Column Temp.: 35.degree. C.
Autosampler Temp.: Ambient
TABLE-US-00002 TABLE 2 Gradient profile for HPLC mobile phases A
and B Initial 60% A 40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00
60% A 40% B
TABLE-US-00003 TABLE 3 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 7.5 phosphate buffer (0.05M,
potassium phosphate monobasic 0.68%/NaOH 0.164%) Media Volume 900
mL Media Temperature 37.0 .+-. 0.5.degree. C. Sampling Time Points
1, 3, 6, 9 and 12 hours Sampling Volume 10 mL without media
replacement (Use 10 .mu.m Full-flow Filter)
FIG. 1 illustrates zero-order release kinetics over 12 hours for
TMD from the hydrophilic matrix containing naproxen sodium with and
without docusate sodium. Prototype 4 contains no DSS, indicating
that the surfactant is not critical to achieving linear release
kinetics. Prototypes 5-8 reveal that the addition of surfactant
into the hydrophilic matrix does impact the rate and extent of
release, with higher DSS levels showing a slower release rate and a
lower extent of release at 12 hours. Regardless of DSS level, all
dissolution profiles in the presence of naproxen sodium are
zero-order.
To further illustrate the importance of naproxen sodium and DSS to
the release kinetics of TMD from the hydrophilic matrix, FIG. 2
shows dissolution profiles for several formulations in which key
components have been added or removed. Prototype 1 shows the
release of TMD from the hydrophilic matrix in the absence of
naproxen sodium and DSS. This formulation shows the largest extent
of release, however, the release profile is non-linear, indicating
that zero-order release is not achieved. Prototypes 2 and 3 show
the release profile of TMD at increasing levels of DSS (15 and 100
mg, respectively), revealing that surfactant level can also be used
to control the rate and extent of TMD release when the NSAID salt
is absent from the hydrophilic matrix. Prototypes 6 and 8 show TMD
release profiles at the same two DSS concentrations (15 and 100 mg,
respectively) in the presence of naproxen sodium. Here, the
addition of the NSAID salt to the matrix increases the rate and
extent of TMD release, while also causing the release rate to
become zero-order.
Example 2
Preparation of Sustained-Release Hydrophilic Matrix Tablets
Containing Hydrocodone Bitartrate (HCB), Naproxen Sodium (NAP), and
Docusate Sodium (DSS) at Benchtop Scale
Each hydrophilic matrix tablet lot was produced by dry-blending the
active substance(s) and excipients together followed by direct
compression. The blending process involved two steps. The HCB and
NAP (when present) were blended together with all excipients except
the Methocel K4M Premium which was later added and blended during
the second step. Blending was accomplished by first dispensing the
powdered components into a stainless steel pan. The components were
then mixed together using a stainless steel spatula to affect
homogenization of the blend. After approximately 2-3 minutes of
mixing, the powders were transferred to a stainless steel 40 mesh
screen where they were pushed through using a plastic sieve
scraper. The pass through was collected in a separate stainless
steel pan. The mixing and sieving processes were then repeated.
Each blending step required two mixing and two sieving processes.
After the final step, the dry blend was transferred to a HDPE bag.
Aliquots of the blend were massed out using an analytical balance
and were compressed using a GlobePharma MTCM-1 hand tablet press.
Lots without NAP were compressed using 0.3125-inch round, concave
Natoli tooling (HOB No. 91300), while lots containing NAP were
compressed using 0.3750-inch round, concave Natoli tooling (HOB No.
91380). The compression force was varied until a tablet breaking
force of 14-16 kPa was consistently achieved.
TABLE-US-00004 TABLE 4 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Naproxen Granular Hydrocodone
Methocel Avicel PH- Sodium Docusate Total Bitartrate K4M (Dow 302
(FMC (Albemarle Sodium (Cytec Tablet Lot No. (Mallinckrodt)
Chemical) Biopolymer) Corp.) Industries, Inc.) Mass (mg) Prototype
1 15.0 120.0 45.0 180.0 Prototype 2 15.0 120.0 45.0 17.6 197.6
Prototype 3 15.0 120.0 45.0 117.7 297.7 Prototype 4 15.0 120.0 45.0
220.0 400.0 Prototype 5 15.0 120.0 45.0 220.0 8.8 408.8 Prototype 6
15.0 120.0 45.0 220.0 17.6 417.6 Prototype 7 15.0 120.0 45.0 220.0
29.4 429.4 Prototype 8 15.0 120.0 45.0 220.0 117.7 517.7
USP Apparatus 2 was used for the dissolution testing of the
prototype tablets produced. The dissolution samples were assayed
for HCB using HPLC with UV detection at 280 nm. The system
parameters for both the chromatographic and dissolution analysis
are shown below. System: Waters Alliance 2487 HPLC System Column:
Phenomenex Jupiter C18, 250.times.4.6 mm ID, 5.mu., 300 .ANG. Part
No.: 00G-4053-EO Detector: UV detector, 280 nm Mobile Phase A:
94.7/5.0/0.3 (v/v/v) water/methanol/TFA Mobile Phase B: Pure
methanol Method Type: Gradient Flow Rate: 1.5 mL/min Injection
Volume: 30 .mu.L Run Time: 11 minutes (11.01-13.00 minutes is
reequilibration) Peakwidth: >0.1 min Column Temp.: 35.degree. C.
Autosampler Temp.: Ambient
TABLE-US-00005 TABLE 5 Gradient profile for HPLC mobile phases A
and B Initial 90% A 10% B 10.00 10% A 90% B 11.00 10% A 90% B 11.01
90% A 10% B 13.00 90% A 10% B
TABLE-US-00006 TABLE 6 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 7.5 phosphate buffer (0.05M,
potassium phosphate monobasic 0.68%/NaOH 0.164%) Media Volume 900
mL Media Temperature 37.0 .+-. 0.5 C. Sampling Time Points 1, 3, 6,
9 and 12 hours Sampling Volume 3 mL without media replacement (Use
10 .mu.m Full-flow Filter)
FIG. 3 illustrates zero-order release kinetics over 12 hours for
HCB from the hydrophilic matrix containing naproxen sodium with and
without docusate sodium. Prototype 4 contains no DSS, indicating
that the surfactant is not critical to achieving linear release
kinetics. Prototypes 5-8 reveal that the addition of surfactant
into the hydrophilic matrix does impact the rate and extent of
release, however, the rate and extent of release do not trend with
surfactant level (as was observed for the TMD examples). The HCB
tablets were compressed using a single-station press, making it
difficult to control the dwell time. As a result, large variations
in tablet hardness were observed (10-18 kP) for identical
compression forces. It is hypothesized that this variation in
tablet hardness could impact water uptake and swelling rates,
resulting in the hysteresis observed in FIG. 3. Regardless of DSS
level, all dissolution profiles in the presence of naproxen sodium
are zero-order.
To further illustrate the importance of naproxen sodium and DSS to
the release kinetics of HCB from the hydrophilic matrix, FIG. 4
shows dissolution profiles for several formulations in which key
components have been added or removed. Prototype 1 shows the
release of HCB from the hydrophilic matrix in the absence of
naproxen sodium and DSS. This formulation shows the largest extent
of release, however, the release profile is non-linear, indicating
that zero-order release is not achieved. Prototypes 2 and 3 show
the release profile of HCB at increasing levels of DSS (15 and 100
mg, respectively), revealing that surfactant level can also be used
to control the rate and extent of HCB release when the NSAID salt
is absent from the hydrophilic matrix. Prototypes 6 and 8 show HCB
release profiles at the same two DSS concentrations (15 and 100 mg,
respectively) in the presence of naproxen sodium. Here, the
addition of the NSAID salt to the matrix increases the rate and
extent of HCB release, while also causing the release rate to
become zero-order.
Example 3
Demonstration of the Abuse-Deterrent Features of Prototype
Formulations Containing Dextromethorphan Hydrobromide (DXM),
Naproxen Sodium (NAP) and Docusate Sodium (DSS)
Dose-Dumping
The abuse-deterrent characteristics of matrix tablets containing
dextromethorphan hydrobromide (DXM) (used herein as an opioid
surrogate), naproxen sodium (NAP), and docusate sodium (DSS) was
demonstrated by performing hydroalcoholic in vitro dissolution and
an independent small-volume extraction experiment.
DXM was chosen as an opioid surrogate due to its chemical,
physical, and structural similarities to the opioid analgesics
useful in the practice of the present invention.
##STR00013##
NAP and DSS were selected because these two compounds represent a
suitable NSAID salt and anionic surfactant, respectively, in the
practice of the present invention.
The hydroalcoholic "dose dumping" experiment investigates the in
vitro opioid (or opioid surrogate) release behavior in the presence
of alcohol. The experiment models ingestion of a tablet with the
concomitant use of alcoholic beverages (i.e., ethanol).
Each hydrophilic matrix tablet lot was produced by dry-blending the
active substance(s) and excipients together followed by direct
compression. The DXM and NAP were added together with all
excipients in an HDPE bag. Blending was accomplished by manually
mixing the contents of the bag for five minutes. Aliquots of the
blend were massed out using an analytical balance and were
compressed using a Manesty DC16 press. Each tablet aliquot was
added to the die manually and compressed at a speed of 5 rpm.
Prototypes 1, 2, and 3 were compressed using 0.3750 in. round,
concave Natoli tooling (HOB #91380). The compression force was
varied until a tablet breaking force of 14-16 kPa was consistently
achieved.
TABLE-US-00007 TABLE 7 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Dextromethorphan Methocel
Naproxen Granular Total Hydrobromide K4M Avicel PH- Sodium Docusate
Tablet (Wockhardt (Dow 302 (FMC (Albemarle Sodium (Cytec Mass Lot
No. Limited) Chemical) Biopolymer) Corp.) Industries, Inc.) (mg)
Prototype 1 15.0 120.0 45.0 220.0 17.6 417.6 Prototype 2 15.0 120.0
45.0 220.0 29.4 429.4 Prototype 3 15.0 120.0 45.0 220.0 58.8
458.8
In order to assess the potential for "dose dumping," the
dissolution method was modified by changing the media to 0.1N HCl
with varying levels of alcohol (ethanol). USP Apparatus 2 was used
for the dissolution testing of the prototype tablets. The
dissolution samples were assayed for DXM using HPLC with UV
detection at 280 nm. The system parameters for both the
chromatographic and dissolution analysis are shown below. System:
Agilent 1100 series HPLC system Column: Phenomenex Jupiter C18,
250.times.4.6 mm ID, 5.mu., 300 .ANG. Part No.: 00G-4053-EO
Detector: UV detector, 280 nm Mobile Phase A: 94.7/5.0/0.3 (v/v/v)
water/methanol/TFA Mobile Phase B: Pure methanol Method Type:
Gradient Flow Rate: 1.5 mL/min Injection Volume: 30 .mu.L Run Time:
8.00 minutes (8.01-10.00 minutes is reequilibration) Peakwidth:
>0.1 min Column Temperature: 35.degree. C. Autosampler temp:
Ambient
TABLE-US-00008 TABLE 8 Gradient profile for HPLC mobile phases A
and B Initial 60% A 40% B 8.00 10% A 90% B 8.01 60% A 40% B 10.00
60% A 40% B
TABLE-US-00009 TABLE 9 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 1.2 USP buffer pH 1.2 USP buffer
(5% ethanol) pH 1.2 USP buffer (20% ethanol) Media Volume 900 mL
Media Temperature 37.0 .+-. 0.5 C. Sampling Time Points 1, 3, 6, 9
and 12 hours Sampling Volume 8 mL without media replacement (Use 10
.mu.m Full-flow Filter)
The purpose of this investigation was to measure the integrity of
the dosage formulation using acidic, hydroalcoholic dissolution
media. For this experiment, intact tablets were evaluated.
Prototype 1 was evaluated since this formulation is expected to
show significantly greater DXM release over 12 hours compared to
Prototypes 2 and 3 based on evaluation of previous formulations of
similar composition.
Dissolution profiles are provided in FIG. 5. The results
demonstrate that "dose dumping" does not occur, even with a 20%
ethanol level in the dissolution media. In addition, zero-order
release is maintained from 0-20% ethanol.
Opioid Extraction
The small-volume extraction experiment models the attempted
extraction of opioid that a substance abuser might undertake. In
this experiment, tablets were crushed and extracted with two common
solvents, water and 40% alcohol. A single tablet was crushed and
stirred with a small volume of solvent (50 mL). At time points of
30 minutes and 12 hours, aliquots were removed and assayed for both
DXM and docusate. Prior to HPLC analysis the aliquots were filtered
using a 10 .mu.m full-flow filter and subsequently centrifuged at
1000 rpm for 30 minutes. The supernatant from this procedure was
filled directly into HPLC vials for analysis. The HPLC assay for
DXM has been described previously. The following HPLC method was
developed to assay docusate: System: Agilent 1100 series HPLC
system Column: YMC-Pack CN, 250 mm.times.4.6 mm ID, 5 .mu.m, 120
.ANG. Part number: CN12S052546WT Detector: UV detector, 225 nm
Mobile Phase A: 0.02M tetrabutylammonium hydrogen sulfate Mobile
Phase B: Pure acetonitrile Method Type: Isocratic 40% A/60% B Flow
Rate: 1.5 mL/min Injection Volume: 10 .mu.L Run Time: 5 minutes
Peakwidth: >0.1 min Column Temperature: 45.degree. C.
Autosampler temp: Ambient
TABLE-US-00010 TABLE 10 Simultaneous Release of Dextromethorphan
Hydrobromide and Docusate Sodium From Crushed Tablets to Assess
Abuse Potential DXM Docusate DXM Docusate Released Released
Released Released Extraction in 30 in 30 in 12 in 12 Formulation
Solvent minutes minutes hours hours Prototype 1 Water 58% 80% 47%
61% Prototype 1 Alcohol 93% 91% 100% 98% 40% Prototype 2 Water 35%
47% 35% 47% Prototype 2 Alcohol 95% 93% 114% 108% 40% Prototype 3
Water 52% 48% 50% 43% Prototype 3 Alcohol 68% 67% 102% 95% 40%
The data (Table 10) demonstrates the simultaneous release of DXM
and docusate from formulations containing different levels of
docusate (Table 7). This data shows that extraction and separation
of DXM and docusate from these formulations would require advanced
chemical knowledge and substantial effort, and would likely be
time-consuming. The commingling of DXM and docusate would make
injection of extracted solutions unattractive to an abuser, and
potentially harmful. Additionally, drying the solution to create a
solid would be of no benefit to a drug abuser, as the solid would
be impure and contain irritating docusate. It is expected that
similar results would be obtained for formulations according to the
present invention that comprise an opioid analgesic.
The complete disclosures of the patents, patent documents, and
publications cited herein are incorporated by reference in their
entirety as if each were individually incorporated. Various
modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention. It should be understood that
this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein.
* * * * *
References